The objective of this project is to understand the biochemical mechanisms for the target organ toxicity of anticancer drugs. These studies have focused on two main areas of research: 1) the first project deals with the mechanism for the renal toxicity of MeCCNU and related nitrosoureas (i.e., CCN, BCNU, chlorozotocin); and 2) the second study involves investigations on the use of buthionine sulfoximine as a thiol modulating agent in cancer chemotherapy. Studies completed this year have demonstrated that: a) carbamyflation-mediated reactions may not be necessary to nephrotoxicity to develop following the administration of nitrosourea anticancer agents; b) the alkylation of kidney DNA may be an important cellular target for nitrosourea nephrotoxicity; c) glutathione plays an important protective role against MeCCNU-induced renal toxicity; d) hepatic drug metabolizing enzymes can activazte MeCCNU and CCNU, but not PCNU, to more polar and more reactive alkylating intermediates which can bind macro-molcules in vitro; e) a liver-derived metabolite of MeCCNU may be responsible for the renal toxicity of the parent nitrosourea; f) in vivo administration of buthionine sulfoximine markedly reduced normal tissue, and L-PAM resistant L1210 tumor glutathione levels following a single dose of BSO, or after a multiple dosing regimen; g) of the normal tissues, the kidney was the most sensitive, and the bone marrow the most resistant, to thiol depletion by BSO; h) BSO increased the renal and hepatic toxicity of MeCCNU in F344 rats and increased the lethality of L-PAM in BDF mice.